Project Summary Alzheimer?s Disease (AD) is a prevalent neurodegenerative disease and the leading cause of age- related dementia. While the pathologic agent that causes AD remains controversial (A? vs. Tau) strong genetic, biochemical, anatomical and electrophysiological evidence have established that A? causes significant synapse loss and blocks induction of long-term potentiation (LTP), a form of plasticity critical for learning and memory. Soluble A? oligomers bind directly to excitatory synapses, but a significant fraction (~30- 40%) of synapses remain unbound. Correspondingly, a subset of synapses are spared from A?-triggered elimination, but the relationship between A? binding and elimination remains a fundamental question. Intriguingly, A?-mediated synapse loss requires activation of NMDA-type glutamate receptors (NMDARs), which gate Ca2+, a key second messenger for important forms of synaptic plasticity, including LTP. While pharmacologically blocking NMDARs prevents A?-induced synapse loss (suggesting that A? induces a gain of NMDAR function), A? also potently blocks LTP, suggesting that A? impairs NMDAR function, or downstream NMDAR signaling. Together, these results provide compelling evidence that NMDARs are a central mediator of A?-induced synaptotoxicity, yet there is a major gap in our understanding of how or whether A? influences NMDAR function. Furthermore, whether local synaptic activity plays a role in A? binding to synapses and whether only those synapses bound by A? are eventually eliminated remain fundamental questions. I will use a novel live cell imaging technique to assess changes in NMDAR function in response to A? at individual synaptic sites.